Plants, like all higher eukaryotes, must control the onset and spread of cell death. Plant biology is replete with examples of developmentally controlled programmed cell death (POD). Additionally, a specialized form of POD in plants, termed the Hypersensitive Response (HR) is tightly correlated with successful recognition of, and response to, pathogen attack. Thus, the HR is potentially an important part of the plant innate immune response. It is, however, unclear what causal role HR plays in stopping pathogen ingress, or whether HR is the consequence of the plant defense response that does kill the pathogen. It is equally unclear whether the genetic control of HR is mechanistically related to, or distinct from, the mechanisms that control plant PCD during development. Additionally, while much is known about the molecular mechanisms of PCD control in animals, essentially nothing is known in plants. This proposal is focused on using Arabidopsis as a genetic model with which to understand the control of HR as an easily definable model for POD in plants. The Arabidopsis genome is fully sequenced and there is little molecular evidence for conservation of key regulators of animal POD at the sequence level. We were among the first to recognize the use of Arabidopsis to genetically dissect cell death control and have made significant contributions to the field. We identified and analyzed a series of mutants that misregulate HR-like cell death in the absence of pathogen. We cloned three key HR regulators all belonging to one gene family: LSD1 and the related genes LOL 1 (LSD One Like 1) and LOL2. We also demonstrated that LSD1 interacts with two classes of transcriptional regulators, that these proteins have biological functions in HA, and that they interact with LSD1 in viva. Based on this previous work, and on the progress reported below, the topics for the Specific Aims, using both forward and reverse genetics, and biochemistry, are: 1. The Arabidopsis LSD1 protein: Control of cell death propagation. 2. isdi signal transduction: Genetic characterization of extragenic isdi suppressors. 3. Molecular homologues of LSD1 also control cell death. 4. The interplay between Isd1 rcd and balances of ROl, NO and SA.